Composition and method for treating skin conditions

ABSTRACT

Compositions and methods for treatment of conditions affecting skin and/or mucosal surfaces of a subject that make use of an imidazoquinoline compound and a retinoid agent are described.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/813,641, filed on Nov. 15, 2017, which is a continuation of U.S.patent application Ser. No. 15/679,495, filed on Aug. 17, 2017, nowissued as U.S. Pat. No. 9,849,123, which is a continuation of U.S.patent application Ser. No. 14/918,661, filed Oct. 21, 2015, now issuedas U.S. Pat. No. 9,763,930, which is a division of U.S. patentapplication Ser. No. 13/288,814, filed Nov. 3, 2011, which claimspriority from U.S. Provisional Application Ser. No. 61/410,110 filedNov. 4, 2010, the entire disclosures of which are incorporated herein bythis reference.

TECHNICAL FIELD

The presently-disclosed subject matter relates to the field of medicaldermatology, and more specifically to the treatment of skin conditions.In particular, the presently-disclosed subject matter relates tocompositions and methods for treating skin conditions, including acombination of an imidazoquinoline compound, and a retinoid agent.

INTRODUCTION

Imidazoquinoline compounds are a family of compounds that have beenshown to provide certain beneficial effects, including antiviral andantitumor effects. For example, imiquimod is an immune-modifying agentthat, when administered topically to a subject, activates localtoll-like receptors to increase interferon and thus the subject's immuneresponse to cells that are over-proliferating due to infection withviral particles or a mutation in the p53 tumor suppressor oncogene.Imiquimod is commercially available as a 3.75% and a 5% cream. It wasinitially used for anogenital warts, and it has now been FDA-approvedfor actinic keratoses on the face and scalp, and for superficial basalcell carcinomas. It has also been used off-label for common warts,molluscum contagiosum, keloids, lentigo maligna, SCC in situ, andextramammary Paget's disease.

While treatment of various skin conditions using imiquimod has shownpromise, its efficacy is limited. In some cases it proves ineffectivebecause it is unable to effectively penetrate the skin. Indeed,imiquimod is not able to effectively penetrate hyperkeratinized(abnormal and normal) skin, and therefore has a limited ability to havea significant effect in areas where thicker skin is present, e.g.,palms, soles, and scalp of a subject. Warts, for example, are oftenfound in areas where thicker skin is present and where imiquimod haslimited efficacy. As such, other less-desirable therapies are employed.Such therapies include use of liquid nitrogen, curettage, laser,cautery, etc. which result in significant pain and local destruction ofinvolved and uninvolved tissue. In addition, very few topical therapieshave demonstrated adequate benefit to be included as a primary therapy.Furthermore, beneficial effects from imiquimod can require lengthytreatment regimens, sometimes 12-16 weeks of treatment are required toachieve results with facial and genital lesions, which can beunsatisfactory from a treatment standpoint, and which can give rise topatient compliance obstacles.

Retinoid agents are a group of compounds that have been shown to have avariety of beneficial effects and have been used in a number ofdermatologic products. For example, tazarotene is a retinoic acidderivative, which acts on the retinoic acid receptor within a cell of asubject to decrease cellular proliferation. Tazarotene is commerciallyavailable as a 0.05% and a 0.1% cream or gel. It is used in diseases ofhyperkeratinization and epithelial cell proliferation, includingpathologies such as acne and psoriasis.

Imidazoquinoline compounds and retinoid agents have been usedindependently for use in treating various skin conditions. Certain skinconditions have also been treated using alternating applications, atdifferent points in time, e.g., application of imiquimod alone on day 1,and then application of tazarotene alone on day 2; however, suchtreatments have shown limited efficacy.

Imidazoquinoline compounds and retinoid agents are relatively difficultto formulate. Imiquimod, for example is well known to be a difficultcompound to solubilize and therefore stability and compatibility issueshave posed problems, not only for finding vehicles that allow imiquimodto be stably-maintained in a formulation for a relevant time periodand/or at a relevant temperature, but packaging can even be a concern.Indeed, with regard to packaging, imiquimod formulations are oftenprovided in sachets rather than tubes, because tubes cannot supportstabile storage of many imiquimod formulations

An imidazoquinoline compound and a retinoid agent have not heretoforebeen administered simultaneously nor have they been combined andprovided together in a single composition. Despite independent use ofproducts, such as commercially-available imiquimod andcommercially-available tazarotene, even for use by an individual inalternating applications at different points in time, there has neverbeen a suggestion to combine the compounds into a single composition.Indeed, with the availability of imidazoquinoline compounds and retinoidagents in separate commercial products, and in view the notorioussolubility challenges associated with imidazoquinoline compounds, whichwould call into question the ability to provide a compatible and stablecomposition including both an imidazoquinoline compound and a retinoidagent, there was no reason to attempt such a combination.

SUMMARY

The present inventor contemplated the simultaneous administration of animidazoquinoline compound with a retinoid agent, such as by using acomposition of the presently-disclosed subject matter. Such acomposition was contemplated to achieve beneficial results as comparedto the administration of an imidazoquinoline compound or a retinoidagent alone or in alternating treatments at different points in time.Without wishing to be bound by theory or mechanism, it is contemplatedthat the retinoid agent of the compositions disclosed herein, with theability to normalize hyperkeratinization, can facilitate penetration ofactive agents delivered therewith. As further contemplated, animidazoquinoline compound, such as imiquimod, has penetrationlimitations that can be overcome by co-administration with a retinoidagent.

As noted herein below, in providing a single composition including bothan imidazoquinoline compound and a retinoid agent, unexpected andbeneficial results are achieved. Beneficial results include increasingpenetration of the imidazoquinoline compound component, which canincrease the efficacy of the composition, and which can allow fortreatment in locations and on lesions where imidazoquinoline compoundand/or retinoid agent treatment was previously ineffective and/orresulted in undue or excessive irritation.

This Summary describes several embodiments of the presently-disclosedsubject matter, and in many cases lists variations and permutations ofthese embodiments. This Summary is merely exemplary of the numerous andvaried embodiments. Mention of one or more representative features of agiven embodiment is likewise exemplary. Such an embodiment can typicallyexist with or without the feature(s) mentioned; likewise, those featurescan be applied to other embodiments of the presently-disclosed subjectmatter, whether listed in this Summary or not. To avoid excessiverepetition, this Summary does not list or suggest all possiblecombinations of such features.

The presently-disclosed subject matter includes compositions,pharmaceutical compositions, kits, and methods useful for treatingconditions of the skin and/or mucosal surfaces of subjects. Thecomposition of the presently-disclosed subject matter includes animidazoquinoline compound; and a retinoid agent. Pharmaceuticalcompositions, methods, and kits of the presently-disclosed subjectmatter make use of the composition of the presently-disclosed subjectmatter.

In some embodiments, the imidazoquinoline compound is imiquimod,resiquimod, sotirimod, or mixtures thereof. In some embodiments, theimidazoquinoline compound is imiquimod. In some embodiments, theimidazoquinoline compound is resiquimod. In some embodiments, theimidazoquinoline compound is sotirimod. In some embodiments, theretinoid agent is selected from the group consisting of: retinol,retinal, retinyl acetate, retinaldehyde, retinyl palmitate, retinoicacid, retinyl propionate, retinyl linoleate, dehydroretinol, eretinate,eretrin, motretinide, tazarotene, isotretinoin, tretinoin, adapalene,bexarotene, fenretinide, and alitretinoin. In some embodiments, theretinoid agent is tazarotene. In some embodiments, the imidazoquinolinecompound is selected from the group consisting of: imiquimod,resiquimod, and sotirimod; and the retinoid agent is selected from thegroup consisting of: retinol, retinal, retinyl acetate, retinaldehyde,retinyl palmitate, retinoic acid, retinyl propionate, retinyl linoleate,dehydroretinol, eretinate, eretrin, motretinide, tazarotene,isotretinoin, tretinoin, adapalene, bexarotene, fenretinide, andalitretinoin. In some embodiments, the imidazoquinoline compound isimiquimod and the retinoid agent is tazarotene.

In some embodiments, the composition further comprises additionalingredients. Such ingredients can include, for example, salicylic acid,urea, an alpha hydroxyl acid, and a beta hydroxyl acid. In someembodiments, the composition includes salicylic acid. In someembodiments, the composition includes urea. In some embodiments, thecomposition includes an alpha hydroxyl acid. In some embodiments, thecomposition includes a beta hydroxyl acid.

In some embodiments, the composition is provided for the treatment of acondition affecting the skin and/or mucosal surfaces of a subject.

In some embodiments, the composition is provided for the treatment of acondition affecting the skin of a subject. In some embodiments, thecomposition is provided for the treatment of a condition affecting themucosal surfaces of a subject.

In some embodiments, the condition is selected from a wart, molluscumcontagiosum, a keloid, and a skin cancer.

In some embodiments, the condition is a wart. In some embodiments, thewart is caused by a papillomavirus. In some embodiments, the wart iscaused by a human papollomaviruses (HPV). In some embodiments, the wartis selected from: verruca vulgaris (common wart), verruca plana (flatwart) condyloma acuminatum or verruca acuminate (genital wart), andverruca pedis (plantar wart).

In some embodiments, the condition is Molluscum contagiosum.

In some embodiments, the condition is a keloid scar. In someembodiments, the condition is a hypertrophic scar.

In some embodiments, the condition is a skin cancer. In someembodiments, the skin cancer is a premalignant skin cancer. In someembodiments, the skin cancer is a malignant skin cancer. In someembodiments, the skin cancer is selected from melanoma and non-melanomaskin cancers, actinic keratoses, basal cell carcinomas, squamous cellcarcinoma-in-situ or Bowen's disease, melanoma in-situ, and otherunresectable carcinomas. In some embodiments, the skin cancer is actinickeratoses. In some embodiments, the skin cancer is a primary skincancer. In some embodiments, the skin cancer is a secondary skin cancer.In some embodiments, the skin cancer is selected from: cutaneous T-celllymphoma, extramammary Paget's disease, lentigo maligna, cutaneousmelanoma metastases, and cutaneous leishmaniasis.

In some embodiments, the subject is a human. In some embodiments, thesubject is a transplant patient. In some embodiments, the subject isreceiving antirejection therapy following a transplant.

In some embodiments, the retinoid agent is provided in the compositionat a final concentration between about 1% (wt/wt) and about 0.001%(wt/wt). In some embodiments, the retinoid agent is provided in thecomposition at a final concentration between about 1% (wt/wt) and about0.001% (wt/wt). In some embodiments, the retinoid agent is provided inthe composition at a final concentration between about 1% (wt/wt) andabout 0.025% (wt/wt). In some embodiments, the retinoid agent isprovided in the composition at a final concentration between about 0.5%(wt/wt) and about 0.01% (wt/wt).

In some embodiments, the retinoid agent is tazarotene provided in thecomposition at a final concentration between about 1% (wt/wt) and about0.001% (wt/wt). In some embodiments, the tazarotene is provided in thecomposition at a final concentration between about 1% (wt/wt) and about0.001% (wt/wt). In some embodiments, the tazarotene is provided in thecomposition at a final concentration between about 1% (wt/wt) and about0.025% (wt/wt). In some embodiments, the tazarotene is provided in thecomposition at a final concentration between about 0.5% (wt/wt) andabout 0.01% (wt/wt). In some embodiments, the tazarotene is provided ata concentration of about 1% (wt/wt). In some embodiments, the tazaroteneis provided at a concentration of about 0.5% (wt/wt). In someembodiments, the tazarotene is provided at a concentration of about 0.1%(wt/wt). In some embodiments, the tazarotene is provided at aconcentration of about 0.05% (wt/wt). In some embodiments, thetazarotene is provided at a concentration of about 0.01% (wt/wt). Insome embodiments, the tazarotene is provided at a concentration of about0.005% (wt/wt). In some embodiments, the tazarotene is provided at aconcentration of about 0.001% (wt/wt).

In some embodiments, the imidazoquinoline compound is provided in thecomposition at a final concentration between about 10% (wt/wt) and about0.1% (wt/wt). In some embodiments, the imidazoquinoline compound isprovided in the composition at a final concentration between about 7%(wt/wt) and about 3% (wt/wt).

In some embodiments, the imidazoquinoline compound is imiquimod providedin the composition at a final concentration between about 10% (wt/wt)and about 0.1% (wt/wt). In some embodiments, the imiquimod is providedin the composition at a final concentration between about 7% (wt/wt) andabout 3% (wt/wt). In some embodiments, the imiquimod is provided at aconcentration of about 10% (wt/wt). In some embodiments, the imiquimodis provided at a concentration of about 5% (wt/wt). In some embodiments,the imiquimod is provided at a concentration of about 3.75% (wt/wt). Insome embodiments, the imiquimod is provided at a concentration of about1% (wt/wt). In some embodiments, the imiquimod is provided at aconcentration of about 0.5% (wt/wt). In some embodiments, the imiquimodis provided at a concentration of about 0.1% (wt/wt).

In some embodiments, the composition allows for increased penetration ofthe imidazoquinoline compound. In some embodiments, the compositionincluding a combination of the imidazoquinoline compound and theretinoid agent has a synergistic effect.

In some embodiments, the imidazoquinoline compound and the retinoidagent are provided in formulation that includes a solvent. In someembodiments, the solvent includes isostearic acid. In some embodiments,the solvent further includes alcohol, diethyl sebacate, or mineral oil.

In some embodiments, the composition is substantially stable at atemperature of 50° C. for a period of four (4) weeks. In someembodiments, the composition is substantially stable at a temperature of40° C. for a period of four (4) weeks. In some embodiments, thecomposition is substantially stable at a temperature of 25° C. for aperiod of four (4) weeks. In some embodiments, the composition issubstantially stable following up to three freeze/warm cycles from −20°C. to 40° C.

In some embodiments, the composition is formulated for topical delivery.In some embodiments, the composition is formulated for intralesionalinjection.

As noted herein, the presently-disclosed subject matter includespharmaceutical compositions of the composition described herein,including the compositions as described in this summary and throughoutthis application.

The presently-disclosed subject matter further includes a kit. Such kitsinclude the compositions as described in this summary and throughoutthis application, and a device useful for administration of thecomposition. Such devices can include, for example, a stick, tape, anocclusive applicator, or an occlusive bandage.

The presently-disclosed subject matter further includes a method for thetreatment of a condition affecting skin and/or a mucosal surface of asubject. Such methods include use of the compositions as described inthis summary and throughout this application. The method includesadministering an effective amount of the composition to the subject. Insome embodiments, the composition is administered to an affected site onthe skin and/or mucosal surface of the subject. In some embodiments, thecomposition is administered topically. In some embodiments, thecomposition is administered by intralegional injection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a picture of a wart on the heel of a subject prior totreatment using a composition of the presently-disclosed subject matter.

FIG. 1B is a picture of the heel of the subject of FIG. 1A followingtreatment using a composition of the presently-disclosed subject matter.

FIG. 2 is a bar graph showing cumulative penetration of Imiquimodfollowing 24 hours of topical exposure in calculated ng/cm² penetratedbased on a 5 mg/cm² dose.

FIG. 3 is a time course showing cumulative receptor phase levels ofImiquimod in calculated ng/cm² penetrated based on a 5 mg/cm² dose.

FIG. 4 is a bar graph showing dermal levels of Imiquimod following 24hours of topical exposure in calculated ng/cm² Imiquimod based on a 5mg/cm² dose.

FIG. 5 is a bar graph showing epidermal levels of Imiquimod following 24hours of topical exposure in calculated ng/cm² Imiquimod based on a 5mg/cm² dose.

FIG. 6 is a bar graph showing dermis plus receptor levels of Imiquimodfollowing 24 hours of topical exposure in calculated ng/cm² Imiquimodbased on a 5 mg/cm² dose.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

The details of one or more embodiments of the presently-disclosedsubject matter are set forth in this document. Modifications toembodiments described in this document, and other embodiments, will beevident to those of ordinary skill in the art after a study of theinformation provided in this document. The information provided in thisdocument, and particularly the specific details of the describedexemplary embodiments, is provided primarily for clearness ofunderstanding and no unnecessary limitations are to be understoodtherefrom. In case of conflict, the specification of this document,including definitions, will control.

While the terms used herein are believed to be well understood by one ofordinary skill in the art, definitions are set forth to facilitateexplanation of the presently-disclosed subject matter.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the presently-disclosed subject matter belongs.Although any methods, devices, and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresently-disclosed subject matter, representative methods, devices, andmaterials are now described.

Following long-standing patent law convention, the terms “a”, “an”, and“the” refer to “one or more” when used in this application, includingthe claims. Thus, for example, reference to “a cell” includes aplurality of such cells, and so forth.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as reaction conditions, and so forth usedin the specification and claims are to be understood as being modifiedin all instances by the term “about”. Accordingly, unless indicated tothe contrary, the numerical parameters set forth in this specificationand claims are approximations that can vary depending upon the desiredproperties sought to be obtained by the presently-disclosed subjectmatter.

As used herein, the term “about,” when referring to a value or to anamount of mass, weight, time, volume, concentration or percentage ismeant to encompass variations of in some embodiments ±20%, in someembodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, insome embodiments ±0.5%, and in some embodiments ±0.1% from the specifiedamount, as such variations are appropriate to perform the disclosedmethod.

As used herein, ranges can be expressed as from “about” one particularvalue, and/or to “about” another particular value. It is also understoodthat there are a number of values disclosed herein, and that each valueis also herein disclosed as “about” that particular value in addition tothe value itself. For example, if the value “10” is disclosed, then“about 10” is also disclosed. It is also understood that each unitbetween two particular units is also disclosed. For example, if 10 and15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

The presently-disclosed subject matter includes compositions and methodsfor using such compositions for the treatment of a condition affectingthe skin and/or mucosal surfaces of a subject. Compositions of thepresently-disclosed subject matter include an imidazoquinoline compoundand a retinoid agent. In some embodiments, the compositions arepharmaceutical compositions. Methods of the presently-disclosed subjectmatter include administering an effective amount of a compositioncomprising an imidazoquinoline compound and a retinoid agent to asubject. The presently-disclosed subject matter includes use of thecompositions disclosed herein for the treatment of a condition affectingthe skin and/or mucosal surfaces of a subject.

The presently-disclosed subject matter overcomes problems associatedwith past formulations of imidazoquinoline compounds having limitedefficacy. The presently-disclosed subject matter allows for thetreatment of areas that before would have been too thick or unresponsiveto an imidazoquinoline compound alone (or an imidazoquinoline compoundand a retinoid agent in alternating doses at different points in time).The presently-disclosed subject matter provides an alternative todestructive and painful therapies, e.g., liquid nitrogen, curettage,laser, cautery, surgical removal, etc. for certain skin conditions.

Furthermore, the composition of the presently-disclosed subject mattercan be useful for treating a condition affecting the a mucosal surfaceof a subject. Heretofore, retinoids, such as tazarotene, have nottypically been used on mucosal surfaces due to accompanying irritation.However, as described in the Examples, the compositions of thepresently-disclosed subject matter have unexpected superior results thatallow for efficacy at lower concentrations of tazarotene than havepreviously been used commercially. Such low concentrations decrease thelikelihood of irritation to the subject such that embodiments of thecompositions of the presently-disclosed subject matter are contemplatedfor use on mucosal surfaces such as the mouth or genitalia. For example,it is contemplated that a composition of the presently-disclosed subjectmatter could be provided in a cervical cap to treat a viral lesion,without the need to surgically treat the lesion. Surgical treatment ofsuch lesions can involve removal of a portion of the cervix, resultingin severe consequences, such as a difficulty or an inability to maintaina pregnancy.

Without wishing to be bound by theory or mechanism, it is believe thatthe simultaneous administration of an imidazoquinoline compound and aretinoid agent in the composition described herein allows for increasedpenetration of the imidazoquinoline compound, thereby increasing theefficacy of the imidazoquinoline compound in locations and on lesionswhere it was previously ineffective or insufficiently effective. Forexample, the inability of imiquimod to penetrate hyperkeratinized(abnormal and normal) skin to the toll-like receptors of the dermis haslimited its ability to have a significant effect in areas of wherethicker skin is present, e.g., palms, soles, and scalp of a subject.Verrucae (warts) are often found on the palms, soles, and in periungualareas where imiquimod is of limited efficacy.

The term “increased penetration,” as used herein with reference topenetration of an imidazoquinoline compound, refers to an increase thatis affected by the combination of the imidazoquinoline compound with theretinoid agent in accordance with the presently-disclosed subjectmatter. As such, the increase refers to the penetration of theimidazoquinoline compound to a site of administration, e.g., lesion,when administered without concurrent administration of a retinoid agent,as compared to the penetration of the imidazoquinoline compound to asite of administration when the composition of the presently-disclosedsubject matter is administered. Penetration can be assessed, forexample, using Franz diffusion cells, as described in the followingreferences, all of which are incorporated herein by this reference:DePaula, Martins, and Bentley, “Development and validation of HPLCmethod for imiquimod determination in skin penetration studies,” BiomedChromatogr 22(12): 1416-23 (2008); Owens M L, Bridson W E, Smith S L,Myers J A, Fox T L, and Wells T M, “Percutaneous penetration of Aldaracream, 5% during the topical treatment of genital and perianal warts,”Prim Care Update Ob Gyns. 5(4):151 (1998).

As used herein, the term “imidazoquinoline compound” is inclusive ofimiquimod (1-(2-methylpropyl)-1H-imidpzo[4,5-c]quinolin-4-amine),resiquimod(4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoli-ne-1-ethanol),sotirimod(2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine),and analogs thereof. The term “imidazoquinoline compound” is furtherinclusive of other imidazoquinoline compounds and derivatives thereofknown to those of ordinary skill in the art, including those describedin Stanley (2002) Clin. Exp. Dermatol. 27(7):571-577; Jones (2003) Curr.Opin. Investig. Drugs 4(2):214-218; and U.S. Pat. Nos. 4,689,338;5,389,640; 5,268,376; 4,929,624; 5,266,575; 5,352,784; 5,494,916;5,482,936; 5,346,905; 5,395,937; 5,238,944; and 5,525,612; and U.S.Patent Application Publication Nos. 2008/0213308; 2009/0182004;2009/0182005; 2011/0217323; 2011/0245289; and 2011/0250237, each ofwhich is incorporated herein by reference. It is noted thatimidazoquinoline compounds have utility as toll-like receptor agonistsor activators, e.g., TLR-7. In some embodiments, of thepresently-disclosed subject matter, compositions can include a toll-likereceptor agonist and a retinoid agent. Imiquimod, a compound in theimidazoquinoline family has been shown to display both antiviral andantitumor effects (Diebold et al. “Innate antiviral responses by meansof toll-like receptor (TLR)-7-mediated recognition of single-strandedRNA”. Science 204; 303: 1529-1531; Barnetson et al. “Imiquimod inducedregression of clinically diagnosed superficial basal cell carcinoma isassociated with early infiltration by CD4 T cells and dendritic cells”.Clin. Exp. Dermatol 2004; 29: 639-643).

Without wishing being bound by theory or mechanism, Imiquimod appears toact via TLR-7 (Hemmi et al. “Small anti-viral compounds activate immunecells via the TLR 7 MyD88-dependent signaling pathway”. Nat. Immunol2002; 3:196-200). Imiquimod can inhibit the progression of actinickeratosis (AK) into invasive skin cancer, usually squamous cellcarcinoma (SCC). Although imiquimod does not appear to have directantineoplastic activity (Schon et al. “Tumor-selective induction ofapoptosis and the small-molecule immune response modifier imiquimod.” JNatl. Cancer inst. 2003, 95:1138-49), it has shown efficacy against avariety of tumors, including skin tumors.

As used herein the term “retinoid agent” refers to compounds having thegeneral structure of vitamin A (retinol) and variations of thatstructure having a similar biological and pharmacological activity asretinol. Examples of retinoids include, but are not limited to, retinol,retinal, retinyl acetate, retinaldehyde, retinyl palmitate, retinoicacid, retinyl propionate, retinyl linoleate, dehydroretinol, eretinate,eretrin, motretinide, tazarotene, isotretinoin, tretinoin, adapalene,bexarotene, fenretinide, and alitretinoin.

As will be recognized by one of ordinary skill in the art upon study ofthe present document, in some cases it could be desirable to includefurther ingredients in the composition as described herein. Examples ofsuch further ingredients include, but are not limited to salicylic acid,urea, alpha-hydroxy acids, and beta-hydroxy acids. Those of ordinaryskill in the art will immediately recognize that various additionalingredients can be beneficial to provide in certain embodiments of theclaimed composition, e.g., vehicle enhancers such as propylene glycol.

Compositions of the presently-disclosed subject matter are useful forthe treatment of various conditions affecting skin and mucosal surfaces(mouth and genetalia) of a subject. Such conditions include a wart,molluscum contagiosum, a keloid, and a skin cancer.

The term “wart” as used herein refers to a growth caused by apapillomavirus at any location on a subject, and is inclusive of, butnot limited to, warts caused by human papollomaviruses (HPV), such as,verruca vulgaris (common wart), verruca plana (flat wart) condylomaacuminatum or verruca acuminate (genital wart), and verruca pedis(plantar wart).

Molluscum contagiosum is an infection caused by a group of viruses inthe Pox-viridae family, known as mulluscum contagiosum viruses (MCV).

The term “keloid” as used herein is inclusive of a keloid scar resultingfrom an overgrowth of scar tissue that occurs at the site of a skininjury. Although the term keloid is used to refer to refer an overgrowthof a scar having a tendency to migrate beyond the boundaries of theoriginal skin injury, and hypertrophic scar is a term used to refer toraised scars that do not so-migrate, as used herein, the term “keloid”is inclusive of both keloid scars and hypertrophic scars, both of whichare characterized by an overgrowth of scar tissue, which can beaccompanied by itching and pain.

As used herein, the term “skin cancer” is used to refer to malignant andpremalignant skin cancers. As such, the term “skin cancer” is inclusiveof melanoma and non-melanoma skin cancers, actinic keratoses, basal cellcarcinomas, squamous cell carcinoma-in-situ or Bowen's disease, melanomain-situ, and other unresectable carcinomas. The term “skin cancer”refers to both primary and secondary cancers of the skin. In thisregard, the term is inclusive of metastatic lesions caused by a primaryskin cancer or another cancer that metastasizes to the skin. Further,the term includes the following nonlimiting examples: cutaneous T-celllymphoma, extramammary Paget's disease, lentigo maligna, cutaneousmelanoma metastases, and cutaneous leishmaniasis. See Jackson andCallen, (In Press) Chapter 128: Immunomodulators. In Bolognia, Jorizzo,and Rapini Dermatology, 3d. Edition, which is incorporated herein bythis reference.

As used herein, the terms “treatment” or “treating” relate to anytreatment of a condition affecting the skin and/or mucosal surface of asubject, including but not limited to prophylactic treatment andtherapeutic treatment As such, the terms treatment or treating include,but are not limited to: inhibiting the progression of a condition;arresting or inhibiting the development of a condition; reducing theseverity of a condition; ameliorating or relieving symptoms associatedwith a condition; and causing a regression of the condition or one ormore of the symptoms associated with the condition. For example,treatment or treating can include, but are not limited to: reduction insize and in thickness and hyperkeratinization; reduced pain; reduceditching; reduced inflammation adjacent to, but not the actual treatmentarea (redness and swelling away from the zone of topical application);reduction in the number of lesions; reduction in the occurrence of newlesions, resolution of lesions beyond the treated area (“field effect”),and reduction in rates of remission, e.g., due to increased immunesurveillance.

As used herein, the term “effective amount” refers to a dosagesufficient to provide treatment for the condition being treated. Thiscan vary depending on the patient, the condition and the treatment beingeffected. The exact amount that is required will vary from subject tosubject, depending on the species, age, and general condition of thesubject, the particular carrier or adjuvant being used, mode ofadministration, and the like. As such, the effective amount will varybased on the particular circumstances, and an appropriate effectiveamount can be determined in a particular case by one of ordinary skillin the art using only routine experimentation.

As used herein, the term “subject” includes both human and animalsubjects. Thus, veterinary therapeutic uses are provided in accordancewith the presently disclosed subject matter. As such, the presentlydisclosed subject matter provides for the treatment of mammals such ashumans and non-human primates, as well as those mammals of importancedue to being endangered, such as Siberian tigers; of economicimportance, such as animals raised on farms for consumption by humans;and/or animals of social importance to humans, such as animals kept aspets or in zoos. Examples of such animals include but are not limitedto: carnivores such as cats and dogs; swine, including pigs, hogs, andwild boars; ruminants and/or ungulates such as cattle, oxen, sheep,giraffes, deer, goats, bison, camels, and horses. The term does notdenote a particular age or sex. Thus, adult and newborn subjects, aswell as fetuses, whether male or female, are intended to be covered.

Contemplated subjects include transplant patients, who can be at riskfor developing a cancer, particularly after extended use ofantirejection therapy. Such subjects can develop squamous cellcarcinomas, for example, which tend to be more aggressive and which area significant cause of death in these subjects. Compositions and methodsof the presently-disclosed subject matter can be used forchemoprevention in such a transplant patient.

As proposed herein, including an imidazoquinoline compound and aretinoid agent in the same composition increases the efficacy of thecomponents of the composition, as compared their efficacy whenadministered separately. In some embodiments, the increase in theefficacy is more than an additive effect, and combination of theimidazoquinoline compound and the retinoid agent can be described ashaving a synergistic effect.

As used herein, “synergy” and “synergistic effect” can refer to anysubstantial enhancement, in a composition of at least two compounds, ofa measurable effect when compared with the effect of a component of thecomposition, e.g., one active compound alone. Measurable effects couldinclude, for example, reduction in thickness and hyperkeratinization,reduced pain, inflammation adjacent to, but not the actual treatmentarea (redness and swelling away from the zone of topical application),fewer or reduction of new lesions demonstrating the immune recognitionrather than simply local irritation, and resolution of verrucae beyondthe treated area demonstrating a systemic recognition or “field effect”

Synergy is a specific feature of a blend of compounds, and is above anybackground level of enhancement that would be due solely to, e.g.,additive effects of any random combination of ingredients. Thiscombination has demonstrated clinically synergistic effects.

In some embodiments, a substantial enhancement of a measurable effectcan be expressed as a coefficient of synergy. A coefficient of synergyis an expression of a comparison between measured effects of acomposition and measured effects of a comparison composition. Thecomparison composition can be a component of the composition, e.g.,imiquimod. In some embodiments, the synergy coefficient can be adjustedfor differences in concentration of the complete composition and thecomparison composition.

Synergy coefficients can be calculated as follows. An activity ratio (R)can be calculated by dividing the % effect of the composition (AB) bythe % effect of the comparison compound (X_(n)), as follows:

R=AB/X _(n)  Formula 1

A concentration adjustment factor (F) can be calculated based on theconcentration (C_(n)), i.e., % (wt/wt) or % (vol/vol), of the comparisoncompound in the composition, as follows:

F=100/C _(n)  Formula 2

The synergy coefficient (S) can then be calculated by multiplying theactivity ratio (R) and the concentration adjustment factor (F), asfollows:

S=(R)(F)  Formula 3

As such, the synergy coefficient (S) can also by calculated, as follows:

S=[(AB/X _(n))(100)]/C _(n)  Formula 4

In Formula 4, AB is expressed as % effect of the blend, X_(n) isexpressed as % effect of the comparison compound (X_(n)), and C_(n) isexpressed as % (wt/wt) or % (vol/vol) concentration of the comparisoncomposition in the blend. Additional information related to calculatingsynergy coefficients can be found in the Examples set forth in thisdocument.

In some embodiments, a coefficient of synergy of about 1.1, 1.2, 1.3,1.4, or 1.5 can be substantial and commercially desirable. In otherembodiments, the coefficient of synergy can be from about 1.6 to about5, including but not limited to about 1.8, 2.0, 2.5, 3.0, 3.5, 4.0, and4.5. In other embodiments, the coefficient of synergy can be from about5 to 50, including but not limited to about 10, 15, 20, 25, 30, 35, 40,and 45. In other embodiments, the coefficient of synergy can be fromabout 50 to about 500, or more, including but not limited to about 50,75, 100, 125, 150, 200, 250, 300, 350, 400, and 450. Any coefficient ofsynergy above 500, 1000, or 5000 is also contemplated within embodimentsof the compositions.

Given that a broad range of synergies can be found in variousembodiments of the invention, it is expressly noted that a coefficientof synergy can be described as being “greater than” a given number andtherefore not necessarily limited to being within the bounds of a rangehaving a lower and an upper numerical limit. Likewise, in someembodiments of the invention, certain low synergy coefficients, or lowerends of ranges, are expressly excluded. Accordingly, in someembodiments, synergy can be expressed as being “greater than” a givennumber that constitutes a lower limit of synergy for such an embodiment.For example, in some embodiments, the synergy coefficient is equal to orgreater than 25; in such an embodiment, all synergy coefficients below25, even though substantial, are expressly excluded.

In some embodiments, synergy or synergistic effect associated with acomposition can be determined using calculations similar to thosedescribed in Colby, S. R., “Calculating synergistic and antagonisticresponses of herbicide combinations,” Weeds (1967) 15:1, pp. 20-22,which is incorporated herein by this reference. In this regard, thefollowing formula can be used to express an expected % effect (E) of acomposition including two compounds, Compound X and Compound Y:

E=X+Y−(X*Y/100)  Formula 5

In Formula 5, X is the measured actual % effect of Compound X in thecomposition, and Y is the measured actual % effect of Compound Y of thecomposition. The expected % effect (E) of the composition is thencompared to a measured actual % effect (A) of the composition. If theactual % effect (A) that is measured differs from the expected % effect(E) as calculated by the formula, then the difference is due to aninteraction of the compounds. Thus, the composition has synergy (apositive interaction of the compounds) when A>E. Further, there is anegative interaction (antagonism) when A<E.

As noted herein, and as known to those of ordinary skill in the art,imidazoquinoline compounds have notorious solubility challenges, callinginto question the ability to provide a compatible and stable compositionincluding both an imidazoquinoline compound and a retinoid agent.Despite such challenges, the present inventor contemplated thecomposition and it was surprisingly discovered that an imidazoquinolinecompound and a retinoid agent could be formulated in a singlecomposition with unexpectedly beneficial properties (See the Examplesfor further details). Such beneficial properties include physicalstability and chemical stability of the composition.

Stability is a specific feature of embodiments of the composition of thepresently-disclosed subject matter. In some embodiments, the compositionis substantially stable at a temperature up to about 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, or 55° C. for a period of about 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days. In someembodiments, the composition is substantially stable at a temperature of50° C. for a period of four (4) weeks. In some embodiments, thecomposition is substantially stable at a temperature of 40° C. for aperiod of four (4) weeks. In some embodiments, the composition issubstantially stable at a temperature of 25° C. for a period of four (4)weeks. In some embodiments, the composition is substantially stablefollowing up to three freeze/warm cycles from −20° C. to 40° C. As usedherein, the term “substantially stable” can refer to physical and/orchemical stability. As will be recognized by those of ordinary skill inthe art, the term “substantially stable” can refer to stability of thecomposition under certain conditions, relative to an initial composition(i.e., when a particular batch of the composition is initiallyprepared). In this regard, as will be recognized by those of ordinaryskill in the art, one manner in which stability of a particularembodiment of the composition can be determined is as follows: preparinga batch of the embodiment of the composition, making an initialassessment of a sample of the composition (control sample), subjecting asample of the composition to conditions of interest (e.g., storage at aparticular temperature for a particular time period) (test sample),making an assessment of the test sample, and comparing the assessment ofthe control sample to the assessment of the test sample. In some cases,to assess stability, it can be desirable to measure and compare theamount of the imidazoquinoline compound and the amount of the retinoidagent in the control sample and in the test same. Calculations can bemade to determine whether the amounts present in the test sample are100%±20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2,1, 0.5, or 0.1% of the amount that is in the control sample.

In some embodiments, a composition is provided wherein theimidazoquinoline compound and the retinoid agent are provided in aparticular ratio relative to one another. For example, in someembodiments the imiquimod and the retinoid agent are provided in a ratioof about 20:1 to about 1:20, wherein the ratio is a weight ratio. Insome embodiments the imiquimod and the retinoid agent are provided in aratio of about 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1,11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4,1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17,1:18, 1:19, or 1:20.

In some embodiments, the imidazoquinoline compound is provided in thecomposition at a final concentration of between about 10% (wt/wt) andabout 0.1% (wt/wt). In some embodiments, imidazoquinoline compound isprovided at a final concentration of between about 7% and about 3%(wt/wt). In some embodiments, the imidazoquinoline compound is providedat a final concentration of about 10.00%, 9.99%, 9.98%, 9.97%, 9.96%,9.95%, 9.94%, 9.93%, 9.92%, 9.91%, 9.90%, 9.89%, 9.88%, 9.87%, 9.86%,9.85%, 9.84%, 9.83%, 9.82%, 9.81%, 9.80%, 9.79%, 9.78%, 9.77%, 9.76%,9.75%, 9.74%, 9.73%, 9.72%, 9.71%, 9.70%, 9.69%, 9.68%, 9.67%, 9.66%,9.65%, 9.64%, 9.63%, 9.62%, 9.61%, 9.60%, 9.59%, 9.58%, 9.57%, 9.56%,9.55%, 9.54%, 9.53%, 9.52%, 9.51%, 9.50%, 9.49%, 9.48%, 9.47%, 9.46%,9.45%, 9.44%, 9.43%, 9.42%, 9.41%, 9.40%, 9.39%, 9.38%, 9.37%, 9.36%,9.35%, 9.34%, 9.33%, 9.32%, 9.31%, 9.30%, 9.29%, 9.28%, 9.27%, 9.26%,9.25%, 9.24%, 9.23%, 9.22%, 9.21%, 9.20%, 9.19%, 9.18%, 9.17%, 9.16%,9.15%, 9.14%, 9.13%, 9.12%, 9.11%, 9.10%, 9.09%, 9.08%, 9.07%, 9.06%,9.05%, 9.04%, 9.03%, 9.02%, 9.01%, 9.00%, 8.99%, 8.98%, 8.97%, 8.96%,8.95%, 8.94%, 8.93%, 8.92%, 8.91%, 8.90%, 8.89%, 8.88%, 8.87%, 8.86%,8.85%, 8.84%, 8.83%, 8.82%, 8.81%, 8.80%, 8.79%, 8.78%, 8.77%, 8.76%,8.75%, 8.74%, 8.73%, 8.72%, 8.71%, 8.70%, 8.69%, 8.68%, 8.67%, 8.66%,8.65%, 8.64%, 8.63%, 8.62%, 8.61%, 8.60%, 8.59%, 8.58%, 8.57%, 8.56%,8.55%, 8.54%, 8.53%, 8.52%, 8.51%, 8.50%, 8.49%, 8.48%, 8.47%, 8.46%,8.45%, 8.44%, 8.43%, 8.42%, 8.41%, 8.40%, 8.39%, 8.38%, 8.37%, 8.36%,8.35%, 8.34%, 8.33%, 8.32%, 8.31%, 8.30%, 8.29%, 8.28%, 8.27%, 8.26%,8.25%, 8.24%, 8.23%, 8.22%, 8.21%, 8.20%, 8.19%, 8.18%, 8.17%, 8.16%,8.15%, 8.14%, 8.13%, 8.12%, 8.11%, 8.10%, 8.09%, 8.08%, 8.07%, 8.06%,8.05%, 8.04%, 8.03%, 8.02%, 8.01%, 8.00%, 7.99%, 7.98%, 7.97%, 7.96%,7.95%, 7.94%, 7.93%, 7.92%, 7.91%, 7.90%, 7.89%, 7.88%, 7.87%, 7.86%,7.85%, 7.84%, 7.83%, 7.82%, 7.81%, 7.80%, 7.79%, 7.78%, 7.77%, 7.76%,7.75%, 7.74%, 7.73%, 7.72%, 7.71%, 7.70%, 7.69%, 7.68%, 7.67%, 7.66%,7.65%, 7.64%, 7.63%, 7.62%, 7.61%, 7.60%, 7.59%, 7.58%, 7.57%, 7.56%,7.55%, 7.54%, 7.53%, 7.52%, 7.51%, 7.50%, 7.49%, 7.48%, 7.47%, 7.46%,7.45%, 7.44%, 7.43%, 7.42%, 7.41%, 7.40%, 7.39%, 7.38%, 7.37%, 7.36%,7.35%, 7.34%, 7.33%, 7.32%, 7.31%, 7.30%, 7.29%, 7.28%, 7.27%, 7.26%,7.25%, 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In someembodiments, the imidazoquinoline compound is provided at a finalconcentration as recited in this paragraph, and is selected fromimiquimod, resiquimod, and sotirimod. In some embodiments, theimidazoquinoline compound is imiquimod, which provided at a finalconcentration as recited in this paragraph. In some embodiments, theimidazoquinoline compound is resiquimod, which provided at a finalconcentration as recited in this paragraph. In some embodiments, theimidazoquinoline compound is sotirimod, which provided at a finalconcentration as recited in this paragraph.

In some embodiments, the retinoid agent is provided in the compositionat a final concentration between about 1% (wt/wt) and about 0.001%(wt/wt). In some embodiments, the retinoid agent is provided at a finalconcentration between about 1% (wt/wt) and about 0.025% (wt/wt). In someembodiments, the retinoid agent is provided at a concentration betweenabout 0.5% (wt/wt) and about 0.01% (wt/wt). In some embodiments, theretinoid agent is provided at a final concentration of about 1.000%,0.999%, 0.998%, 0.997%, 0.996%, 0.995%, 0.994%, 0.993%, 0.992%, 0.991%,0.990%, 0.989%, 0.988%, 0.987%, 0.986%, 0.985%, 0.984%, 0.983%, 0.982%,0.981%, 0.980%, 0.979%, 0.978%, 0.977%, 0.976%, 0.975%, 0.974%, 0.973%,0.972%, 0.971%, 0.970%, 0.969%, 0.968%, 0.967%, 0.966%, 0.965%, 0.964%,0.963%, 0.962%, 0.961%, 0.960%, 0.959%, 0.958%, 0.957%, 0.956%, 0.955%,0.954%, 0.953%, 0.952%, 0.951%, 0.950%, 0.949%, 0.948%, 0.947%, 0.946%,0.945%, 0.944%, 0.943%, 0.942%, 0.941%, 0.940%, 0.939%, 0.938%, 0.937%,0.936%, 0.935%, 0.934%, 0.933%, 0.932%, 0.931%, 0.930%, 0.929%, 0.928%,0.927%, 0.926%, 0.925%, 0.924%, 0.923%, 0.922%, 0.921%, 0.920%, 0.919%,0.918%, 0.917%, 0.916%, 0.915%, 0.914%, 0.913%, 0.912%, 0.911%, 0.910%,0.909%, 0.908%, 0.907%, 0.906%, 0.905%, 0.904%, 0.903%, 0.902%, 0.901%,0.900%, 0.899%, 0.898%, 0.897%, 0.896%, 0.895%, 0.894%, 0.893%, 0.892%,0.891%, 0.890%, 0.889%, 0.888%, 0.887%, 0.886%, 0.885%, 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0.002%, or0.001% (wt/wt). In some embodiments, the retinoid agent is provided at afinal concentration as recited in this paragraph, and is selected fromretinol, retinal, retinyl acetate, retinaldehyde, retinyl palmitate,retinoic acid, retinyl propionate, retinyl linoleate, dehydroretinol,eretinate, eretrin, motretinide, tazarotene, isotretinoin, tretinoin,adapalene, bexarotene, fenretinide, and alitretinoin. In someembodiments, the retinoid agent is retinol, which provided at a finalconcentration as recited in this paragraph. In some embodiments, theretinoid agent is retinal, which provided at a final concentration asrecited in this paragraph. In some embodiments, the retinoid agent isretinyl acetate, which provided at a final concentration as recited inthis paragraph. In some embodiments, the retinoid agent isretinaldehyde, which provided at a final concentration as recited inthis paragraph. In some embodiments, the retinoid agent is retinylpalmitate, which provided at a final concentration as recited in thisparagraph. In some embodiments, the retinoid agent is retinoic acid,which provided at a final concentration as recited in this paragraph. Insome embodiments, the retinoid agent is retinyl propionate, whichprovided at a final concentration as recited in this paragraph. In someembodiments, the retinoid agent is retinyl linoleate, which provided ata final concentration as recited in this paragraph. In some embodiments,the retinoid agent is dehydroretinol, which provided at a finalconcentration as recited in this paragraph. In some embodiments, theretinoid agent is eretinate, which provided at a final concentration asrecited in this paragraph. In some embodiments, the retinoid agent iseretrin, which provided at a final concentration as recited in thisparagraph. In some embodiments, the retinoid agent is motretinide, whichprovided at a final concentration as recited in this paragraph. In someembodiments, the retinoid agent is tazarotene, which provided at a finalconcentration as recited in this paragraph. In some embodiments, theretinoid agent is isotretinoin, which provided at a final concentrationas recited in this paragraph. In some embodiments, the retinoid agent istretinoin, which provided at a final concentration as recited in thisparagraph. In some embodiments, the retinoid agent is adapalene, whichprovided at a final concentration as recited in this paragraph. In someembodiments, the retinoid agent is bexarotene, which provided at a finalconcentration as recited in this paragraph. In some embodiments, theretinoid agent is fenretinide, which provided at a final concentrationas recited in this paragraph. In some embodiments, the retinoid agent isalitretinoin, which provided at a final concentration as recited in thisparagraph.

As noted herein, it will be recognized by one of ordinary skill in theart upon study of the present document that in some cases it could bedesirable to include further ingredients in the composition as describedherein, e.g., salicylic acid, urea, alpha-hydroxy acids, beta-hydroxyacids.

For example, in some embodiments, the composition can additionallyinclude salicylic acid. In some embodiments, the salicylic acid isprovided in a final concentration of about 0.5, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 15, 20, 30, 35, 40, 45, 50, 55, 60, 65, or 70% (wt/wt). Withoutwishing to be bound by theory or mechanism, the addition of salicylicacid can further increase the efficacy of some embodiments. Thesalicylic acid can result in epidermal desquamation of thehyperkeratosis, such that penetration of the composition is increased.It can also dilute or reduce the concentration of the retinoid agent, byaltering the ratio of retinoid agent to imidazoquinoline compound (e.g.,5:1, 10:1, 20:1) so as to increase local tolerability and whilemaintaining efficacy.

For another example, in some embodiments, the composition canadditionally include urea. In some embodiments, the urea is provided ina final concentration of about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20, 30, 35, 40, 45, 50, 55, 60, 65, or 70% (wt/wt). Without wishing tobe bound by theory or mechanism, the addition of urea can furtherincrease the efficacy of some embodiments. The urea can result inincreased penetration. It can also dilute or reduce the concentration ofthe retinoid agent, by altering the ratio of retinoid agent toimidazoquinoline compound (e.g., 5:1, 10:1, 20:1) so as to increaselocal tolerability and while maintaining efficacy.

For another example, in some embodiments, the composition canadditionally include alpha-hydroxy acid. In some embodiments, thealpha-hydroxy acid is provided in a final concentration of about 0.5, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 35, 40, 45, 50, 55, 60, 65, or70% (wt/wt). Without wishing to be bound by theory or mechanism, theaddition of alpha-hydroxy acid can further increase the efficacy of someembodiments. The alpha-hydroxy acid can result in epidermal desquamationof the hyperkeratosis, such that penetration of the composition isincreased. It can also dilute or reduce the concentration of theretinoid agent, by altering the ratio of retinoid agent toimidazoquinoline compound (e.g., 5:1, 10:1, 20:1) so as to increaselocal tolerability and while maintaining efficacy.

For another example, in some embodiments, the composition canadditionally include beta-hydroxy acid. In some embodiments, thebeta-hydroxy acid is provided in a final concentration of about 0.5, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 35, 40, 45, 50, 55, 60, 65, or70% (wt/wt). Without wishing to be bound by theory or mechanism, theaddition of beta-hydroxy acid can further increase the efficacy of someembodiments. The beta-hydroxy acid can result in epidermal desquamationof the hyperkeratosis, such that penetration of the composition isincreased. It can also dilute or reduce the concentration of theretinoid agent, by altering the ratio of retinoid agent toimidazoquinoline compound (e.g., 5:1, 10:1, 20:1) so as to increaselocal tolerability and while maintaining efficacy.

As will be apparent to one of ordinary skill in the art, furtheringredients, such as vehicle enhancers can be provided in thecomposition of the presently-disclosed subject matter. Examples include,but are not limited to propylene glycol, cocamidopropyl betaine,oleamidoproplyl dimethylamine, propyl gallate, polyethylene glycol, andthe like. Reference is also made to U.S. Patent Application PublicationNo. 2009/0182004, entitled “Imiquimod Formulation,” which isincorporated herein by this reference.

In some embodiments, the composition is formulated for topicaladministration. In some embodiments, the composition can include aconcentration of each active ingredient from about 1 to 30% in a carriersuch as a pharmaceutical cream or gel base. Various formulations fortopical use include, but are not limited to, drops, tinctures, lotions,creams, gels, solutions, ointments, lacquers. It is noted that thecomposition can also be associated with a device that contains thecompositions and various supports and/or vehicles useful for delivery ofthe composition, for example, sticks (pins), tapes, occlusiveapplicators (e.g., cervical cap), and occlusive bandages. Such a devicecan be provided in a kit, together with the composition. The optimalpercentage of the therapeutic agent in each pharmaceutical formulationvaries according to the formulation itself and the therapeutic effectdesired in the specific pathologies and correlated therapeutic.

As noted herein, the presently-disclosed subject matter further includesa method for the treatment of a condition affecting skin and/or amucosal surface of a subject, which includes administering an effectiveamount of a composition, as described hereinabove, to the subject. Insome embodiments, the composition is administered to an affected site onthe skin or the mucosal surface of the subject. In some embodiments, thecomposition is administered topically, which can include directadministration to skin or mucosa, including intranasal, oral, andgenital mucosa. In some embodiments, the composition can be injected,for example, administered by intralesional injection.

The presently-disclosed subject matter is further illustrated by thefollowing specific but non-limiting examples. The following examplesinclude some prophetic examples, as indicated. The following examplesmay include compilations of data that are representative of datagathered at various times during the course of development andexperimentation related to the present invention.

EXAMPLES Example 1—In Vivo Treatment of Warts

A composition including an imidazoquinoline compound; and a retinoidagent was tested in vivo. Imiquimod (5% (wt/wt)) and tazarotene (0.1%(wt/wt) were combined in a 1:1 ratio. The resulting composition wastopically applied to individual warts in approximately 30 patients. Thepatients had various types of warts (thick and thin) in varyinglocations including palms, soles, hands, legs, feet, trunk, andextremities (including periungual). The composition could be usedoccluded or non-occluded, at the patient's option.

With reference to FIGS. 1 and 2, the treatment resulted in markedimprovement and resolution in many cases. This treatment was used withwarts in multiple sites including the arms, legs, hands, feet, facial,and periungual areas with beneficial results. There was completeresolution in about 50% of the patients. There was about a 75%-90%reduction in size and number of warts in about 25% of the patients.There was about a 50%-75% reduction in size and number of warts in about25% of the patients. The time for the patients to respond was about 1week (in 5 of the patients) to about 3 months, with an average time toresponse of about 4-6 weeks. Some patients demonstrated a responseincluding complete resolution without inflammation. The duration ofresponse was shown to be prolonged in complete responders. Another notedbenefit associated with the composition has been the resolution of wartsat locally distant untreated sites (which may be due to increased immunerecognition) as well as the decreased recurrence rate as compared toother modalities.

Patient follow-up showed no major tolerability issues. The compositionwas well-tolerated in the patients receiving treatment, with the mostcommon side effect being a local minor irritation and sometimes a minorvesicular reaction (usually painless). The composition was reported tobe easy to apply, convenient, and effective.

These results are in contrast to the results seen when applyingimiquimod or tazarotene individually, which were not as efficacious. Thecomposition resulted in surprisingly increased efficacy relative to thetreatment with imiquimod or tazarotene individually.

Example 2—In Vivo Treatment of Skin Conditions (Prophetic)

A composition including an imidazoquinoline compound; and a retinoidagent is tested in vivo. The composition is topically applied to sitesdisplaying a skin condition selected from a wart, molluscum contagiosum,a keloid, and a skin cancer, each as defined herein. The treatmentresults in marked improvement and resolution in many cases. The resultsare found to be more efficacious as compared to applying animidazoquinoline compound or a retinoid agent individually.

Example 3—In Vivo Treatment of Skin Conditions Effecting Mucosal Surface(Prophetic)

A composition including an imidazoquinoline compound; and a retinoidagent is tested in vivo. The composition includes a concentration ofretinoid agent (e.g., tazarotene) that is sufficiently low so as not tocause undue irritation to the mucosal surface (e.g., mouth or genitalia)of a patient. The composition is topically applied to sites displaying askin condition selected from a wart, molluscum contagiosum, a keloid,and a skin cancer, each as defined herein. The treatment results inmarked improvement and resolution in many cases. The results are foundto be more efficacious as compared to applying an imidazoquinolinecompound or a retinoid agent individually. Surprisingly, the inclusionof the retinoid agent, even at a concentration sufficiently low so asnot to cause undue irritation to the mucosal surface, results inunexpected beneficial results.

Example 4—Synergy Coefficient (Prophetic)

An animal model of hyperkeratinized skin is used to test the efficacy ofan exemplary composition and the efficacy of imiquimod for treatingcommon warts. The exemplary composition includes 5% (wt/wt) imiquimodand a 0.1% (wt/wt) tazarotene.

The comparison compound is imiquimod. Administration of the compositionresults in a 100% cure rate, while the treatment with imiquimod resultsin a 60% cure rate.

The activity ratio is calculated as follows:

R=AB/X _(n)=100/60=1.67.

The concentration adjustment factor is calculated as follows:

F=100/C _(n)=100/5=20.

The synergy coefficient is therefore:

S=(R)(F)=(1.67)(20)=33.34; or

S=[(AB/X _(n))(100)]/C _(n)=[(100/60)(100)]/5=33.34

The experiment is repeated, wherein the comparison compound istazarotene. Administration of the composition results in a 100% curerate, while the treatment with tazarotene results in a 40% cure rate.

According to Formula 1, the activity ratio is calculated as follows:

R=AB/X _(n)=100/40=2.5

According to Formula 2, the concentration adjustment factor iscalculated as follows:

F=100/C _(n)=100/0.1=1000

According to Formulae 3 and 4, the synergy coefficient is therefore:

S=(R)(F)=(2.5)(1000)=2500; or

S=[(AB/X _(n))(100)]/C _(n)=[(100/40)(100)]/0.1=2500

Based on the measured % effect of imiquimod (60%) and tazarotene (40%),the expected % effect of the combination is calculated according toFormula 5, as follows:

E=X+Y−(X*Y/100)=60+40−(60*40/100)=76

The actual % effect of the composition is 100% (A=100). BecauseA=100>E=76, the combination has synergy (a positive interaction of thecompounds).

Example 5—Solubility, Compatibility, and Stability of the Composition

The composition feasibility of a composition including both imiquimodand tazarotene was studied. Goals of the study included the following:to determine whether the imidazoquinoline compound and the retinoidagent are compatible with each other, to determine whether commonsolvents could be used to sufficiently dissolve the two ingredients, andto determine whether the resulting composition would be stable. Theability to produce a stable and compatible composition was uncertain atthe outset of these studies, in part, given that imiquimod is well knownto be a challenging molecule.

For this example, isostearic acid (ISA) was selected as a primarysolvent, and the following additional solvents were selected based onmiscibility with ISA and solubility of tazarotene: alcohol (A) (ethylalcohol, USP (190 Proof)), benzyl alcohol (BA), diethyl sebacate (DES),mineral oil (MO), and transcutol (T).

The compositions having solvent blends as outlined in Table 1 wereprepared to evaluate the compatibility of imiquimod (5% wt/wt) andtazarotene (0.1% wt/wt).

TABLE 1 Solvent Blends for to Test Compatibility of Imiquimod andTazarotene 50:50 Isostearic Acid and Alcohol (ISA + A) 50:50 IsostearicAcid and Benzyl Alcohol (ISA + BA) 50:50 Isostearic Acid and DiethylSebacate (ISA + DES) 50:50 Isostearic Acid and Mineral Oil (ISA + MO)50:50 Isostearic Acid and Transcutol (ISA + T)

Control Samples for each solution (T=0) were provided using the initialsamples stored at 5° C., and analyzed after four (4) weeks. Test Samplesof each solution were subjected to the following conditions: 1) storageat 25° C. for four weeks; 2) storage at 40° C. for four weeks; 3)storage at 50° C. for four weeks; and 4) three cycles of freeze/warm(F/W) cycling (−20° C. to 40° C.). The physical stability of each Samplewas observed and the chemical stability of imiquimod and tazarotene ineach Sample was studied using chromatographic techniques.

Information regarding Physical Stability is set forth in Table 2.

TABLE 2 Physical Stability Batch 3 cycles 4 weeks 4 weeks 4 weeks3537-18 Description T = 0 F/W 25° C. 40° C. 50° C. 2 ISA + A pale yellowConforms Conforms Conforms Conforms clear solution 3 ISA + BA paleyellow Conforms Conforms Conforms Conforms clear solution 4 ISA + DESpale yellow Conforms Conforms Conforms Conforms clear solution 5 ISA +MO colorless to Conforms Conforms Conforms Conforms pale yellow, clearsolution 6 ISA + T colorless to Conforms Conforms *pale yellow *paleyellow pale yellow, solution, crystals solution, crystals clear solutionsettled at bottom settled at bottom Note: “Conforms” indicatesappearance meets T = 0 evaluation

Information regarding Chemical Stability is set forth in Tables 3-8.

TABLE 3 Summary of Imiquimod Stability Imiquimod % Label Claim (degs, %Area) 3 cycles 4 weeks 4 weeks 4 weeks Description T = 0 F/W 25° C. 40°C. 50° C. ISA + A 102.3 101.9 102.9 102.1 102.6 (0.08) ISA + BA 101.3101.3 101.5 102.2 101.5 (0.22) (0.26) (0.36) ISA + DES 100.6 101.5 101.1102.1 101.3 ISA + MO 101.4 102.4 101.4 101.7 101.8 ISA + T 102.0 101.9101.5 Not Not nalyzed analyzed Note: Mean values are reported

TABLE 4 Summary of Tazarotene Stability Tazarotene % Label Claim (degs,% Area) Batch 3 cycles 4 weeks 4 weeks 4 weeks 3537-18 Description T = 0F/W 25° C. 40° C. 50° C. 2 ISA + A 101.5 100.3 (0.19)  102.6 100.8(0.18) 99.9 (0.34) 3 ISA + BA 78.6 (0.42) 66.0 (1.35) 76.2 (0.51)  63.8(1.59) 57.8 (1.76) 4 ISA + DES 100.0 99.4 100.8 99.5 99.1 5 ISA + MO100.9 99.9 100.5 98.4 99.1 6 ISA + T 101.6 91.4 (0.49) 100.7 Notanalyzed Not analyzed Note: Mean values are reported

TABLE 5 Tazarotene and Imiquimod Solution Stability Summary ReportImiquimod Tazarotene % Degradation Products % Degradation Products %Description Condition LC (RRT) % Area LC (RRT) Area 50:50 T = 0 100.9 NCNA 100.2 ND NA Isostearic 103.6 ND NA 102.8 ND NA Acid and Freeze/Warm100.8 ND NA 99.3 0.92 0.19 Alcohol (−20° C./40° C. 103.0 ND NA 101.30.92 0.19 4 weeks at 102.7 ND NA 102.6 ND NA 25° C. 103.0 ND NA 102.5 NDNA 4 weeks at 101.4 ND NA 100.3 0.92 0.16 40° C. 102.7 ND NA 101.2 0.920.19 4 weeks at 102.9 1.22 0.08 99.8 0.92 0.32 50° C. 102.2 1.22 0.08100.0 0.92 0.35

TABLE 6 Tazarotene and Imiquimod Solution Stability Summary ReportTazarotene Imiquimod Degradation % Degradation % Products DescriptionCondition LC Products (RRT) % Area LC (RRT) % Area 50:50 T = 0 100.5 NDNA 78.3 0.84 0.41 Isostearic 102.0 ND NA 78.9 0.84 0.42 Acid andFreeze/Warm 100.9 1.71 0.23 65.8 0.84 0.75 Benzyl (−20° C./40° C.) 1.050.53 Alcohol Total: 1.27 101.7 1.71 0.21 66.2 0.84 0.94 1.05 0.48 Total:1.42 4 weeks at 101.7 ND NA 76.3 0.84 0.46 25° C. 101.3 N/D NA 76.0 0.840.55 4 weeks at 102.4 1.71 0.26 63.7 0.84 1.03 40° C. 1.05 0.59 Total:1.62 101.9 1.71 0.25 63.8 0.85 0.97 1.05 0.59 Total: 1.56 4 weeks at101.4 1.71 0.31 57.7 0.84 1.18 50° C. 1.05 0.79 Total: 1.97 101.6 1.710.40 57.9 0.84 1.01 1.05 0.54 Total: 1.55

TABLE 7 Tazarotene and Imiquimod Solution Stability Summary ReportImiquimod Tazarotene Degradation Degradation Description Condition % LCProducts (RRT) % Area % LC Products (RRT) % Area 50:50 T = 0 101.3 ND NA100.5 ND NA Isostearic 99.9 ND NA 99.5 ND NA Acid and Freeze/Warm 101.6ND NA 99.4 ND NA Diethyl (−20° C./40° C.) 101.3 ND NA 99.3 ND NASebacate 4 weeks at 100.9 ND NA 100.8 ND NA 25° C. 101.3 ND NA 100.8 NDNA 4 weeks at 102.3 ND NA 99.7 ND NA 40° C. 101.8 ND NA 99.2 ND NA 4weeks at 101.7 ND NA 99.3 ND NA 50° C. 100.9 ND NA 98.8 ND NA

TABLE 8 Tazarotene and Imiquimod Solution Stability Summary ReportImiquimod Tazarotene Degradation Degradation Description Condition % LCProducts (RRT) % Area % LC Products (RRT) % Area 50:50 T = 0 100.5 ND NA100.3 ND NA Isostearic 102.3 ND NA 101.4 ND NA Acid and Freeze/Warm102.9 ND NA 100.1 ND NA Mineral (−20° C./40° C.) 101.8 ND NA 99.7 ND NAOil 4 weeks at 101.7 ND NA 100.4 ND NA 25° C. 101.0 ND NA 100.5 ND NA 4weeks at 102.1 ND NA 98.8 ND NA 40° C. 101.2 ND NA 97.9 ND NA 4 weeks at101.9 ND NA 99.3 ND NA 50° C. 101.6 ND NA 98.8 ND NA

As reflected by the results presented above, the physical stability ofimiquimod and tazarotene combination is shown for all Samples, with theexception of the samples including isostearic acid and transcutol(ISA+T) stored at high temperatures (40-50° C.).

As also reflected by the results presented above, in all Samplesanalyzed, imiquimod was shown to be chemically stable, based on the factthat the mean assay values remained relatively unchanged from theinitial values over 4 weeks at various temperatures.

As further reflected by the results presented above, Tazarotene ischemically stable in all the solvent blends with the exception ofisostearic acid and benzyl alcohol (ISA+BA), in which it appears that BAhas a negative impact on the chemical stability of tazarotene andappears to result in a temperature dependant loss of tazarotene.Tazarotene stability also appears to be impacted by exposure to F/Wcycling in ISA+T.

To summarize, all analyzed Samples displayed both physical and chemicalstability under certain conditions, including storage at roomtemperature (25° C.). Furthermore, compositions of imiquimod andtazarotene in ISA plus alcohol, diethyl sebacate, or mineral oil wereboth physically and chemically stable under all test conditions,including storage for four weeks at 5° C., 25° C., 40° C., and 50° C.,as well as conditions including three rounds of freeze/warm cycling.

Example 6—In Vitro Percutaneous Absorption Studies Using Human Tissue

To characterize the effect of providing a composition including both animidazoquinoline compound and a retinoid agent on the penetration of thecomposition as compared to an imidazoquinoline compound alone,absorption studies were conducted using human tissue. For the studydescribed in this example, varying concentrations of tazarotene wereevaluated while keeping the concentration of imiquimod constant (5%w/w).

Data from this in vitro skin permeation study indicate a trend in theefficiency of delivery of Imiquimod. Imiquimod delivery, expressed as asum of all the delivery values for each of the three evaluatedcompartments, has a consistent response to the addition of Tazarotene:Delivery of Imiquimod increases with the addition of Tazarotene.

DMSO based controls are used because they usually yield higher deliveryof actives through the skin. In this case, the DMSO control (whichincluded Tazarotene) did not give a higher degree of penetration,indicating that imiquimod delivery is independent of the choice ofsolvent, but instead is due to the addition of tazarotene.

Methods

This in vitro percutaneous absorption study was conducted usingprocedures adapted from the FDA and AAPS Report of the Workshop onPrinciples and Practices of In Vitro Percutaneous Penetration Studies:Relevance to Bioavailability and Bioequivalence (Skelly et al., 1987).All evaluated compositions were prepared by DPSI. The compositions ofall the compositions evaluated in this study are summarized in Table 9.

TABLE 9 Test Samples Sample ID* Description % (w/w) Tazarotene % (w/w)Imiquimod 3537-25-1 Tazarotene (T) 0.10 0.00 3537-25-2 Imiquimod (I)0.00 5.00 3537-25-3 1:500 0.01 5.00 3537-25-4 1:100 0.05 5.00 3537-25-51:50 0.10 5.00 3537-26-1 1:10 0.50 5.00 3537-26-2 1:5 1.00 5.003537-26-3 DMSO 0.10 5.00 3537-28-3** Control - 1:50 *All samples wereprovided in 50:50 Isostearic Acid and Alcohol (ISA + A), except the DMSOControl, which was provided in 80:20 DMSO and Isostearic Acid. **SampleIDs 3537-28-3 is identical to 3537-26-3. Sample IDs 3537-28-3 and3537-25-1 were used as positive and negative controls for Imiquimodpermeation, respectively.

The clinically relevant dose of 5 mg/cm² was applied to dermatomed humanabdominal tissue from a single donor obtained following electivesurgery. The thickness of the tissue ranged from 0.023-0.032 inches(0.584-0.813 mm) with a mean+/−standard deviation in thickness of0.027+/−0.003 inches (0.677+/−0.066 mm) and a coefficient of variationof 10%.

Percutaneous absorption was evaluated using this human abdominal tissuefrom a single donor mounted in Bronaugh flow-through diffusion cells.The cells were maintained at a constant temperature of 32° C. by use ofrecirculating water baths. These cells have a nominal diffusion area of0.64 cm². Fresh receptor phase (PBS, pH 7.4, containing 0.1% sodiumazide and 4% Bovine Serum Albumin) was continuously pumped under thetissue at a flow rate of nominally 0.25 ml/hr and collected in 6-hourintervals. The receptor phase samples were collected in pre-weighedscintillation vials; the post weights were taken at the end of thestudy. Following the 24-hour duration exposure, the composition residingon the tissue surface was removed by tape-stripping with CuDerm D-Squamestripping discs. The epidermis, dermis, and receptor phase samples werelabeled and frozen prior to subsequent analysis of Tazarotene andImiquimod content by LC/MS/MS and ultimate sample disposal.

Tissue permeation and deposition results were statistically evaluatedusing unpaired student's t-tests (significant differences betweencompositions were defined by a p-value of <0.05, at the 95% confidenceinterval).

Results

Epidermis, Dermis, and Receptor.

With reference to Table 10, Column 5, data showing cumulativepenetration of imiquimod based on a 5 mg/cm′ dose is presented aspercent of applied dose (Sub-column A) and calculated ng/cm² following atheroretical dose of 5 mg composition/cm².

With regard to efficiency of delivery, the total amount of imiquimodpresent ranged from 1.93 to 4.07 percent of the applied dose ofImiquimod. Compositions 3537-25-4 and 3537-26-1 had the highestefficiency of delivery with 3.07 and 4.07 percent of the applied dose ofImiquimod, respectively. Composition 3537-25-2, the only compositionthat did not contain tazarotene, exhibited the least efficient deliverywith 1.93 percent of the applied dose.

With regard to total amount of Imiquimod delivered, the calculatedamount ranged from 4833 to 10186 ng/cm². Compositions 3537-25-4 and3537-26-1 had the highest total Imiquimod with 7682 and 10186 ng/cm²,respectively. Composition 3537-25-2, the only composition that did notcontain tazarotene, generated the lowest total levels of Imiquimod, with4833 ng/cm². The data presented in Table 10, Column 5, Sub-column B arepresented graphically in FIG. 2.

TABLE 10 Cumulative Receptor Phase and Tissue Levels of ImiquimodFollowing 24 Hours of Topical Exposure Receptor Content Dermis +Receptor Epidermis + Dermis + at 24 Hours Epidermis Dermis Mean ReceptorMean Calculated Calculated Calculated Calculated Calculated ng/cm² Aping/cm2 Api ng/cm2 Api ng/cm2 Api ng/cm2 Api for for for for forFormulation Formulation Formulation Formulation Formulation Formulation% Dose of % Dose Dose of % Dose Dose of % Dose Dose of % Dose Dose of IDDose Applied 5 mg/cm² Applied 5 mg/cm2 Applied 5 mg/cm2 Applied 5 mg/cm2Applied 5 mg/cm2 A) ID: 3537- Mean 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 25-1 SD 0.00 0.00 0.00 0.00 0.00 0.00 % CV N/A N/A N/AN/A N/A N/A B) ID: 3537- Mean 0.018 46.2 1.80 4492 0.118 295 0.136 3411.93 4833 25-2 SD 0.008 20.5 0.52 1292 0.028 71 % CV 44 44 29 29 24 24C) ID: 3537- Mean 0.018 44.2 2.40 5991 0.186 466 0.204 510 2.60 650125-3 SD 0.006 16.0 0.39 985 0.097 243 % CV 36 36 16 16 52 52 D) ID:3537- Mean 0.016 39.1 2.79 6971 0.269 672 0.284 711 3.07 7682 25-4 SD0.005 13.3 1.00 2489 0.217 543 % CV 34 34 36 36 81 81 E) ID: 3537- Mean0.015 37.2 2.53 6331 0.193 483 0.208 520 2.74 6851 25-5 SD 0.005 12.50.79 1982 0.102 255 % CV 34 34 31 31 53 53 F) ID: 3537- Mean 0.016 40.33.76 9405 0.296 741 0.312 781 4.07 10186 26-1 SD 0.005 11.9 1.33 3360.164 410 % CV 29 29 35 35 55 55 G) ID: 3537- Mean 0.024 60.1 1.93 48300.186 466 0.211 526 2.14 5356 26-2 SD 0.028 70.8 0.55 1380 0.080 200 %CV 118 118 29 29 43 43 H) ID: 3537- Mean 0.026 63.9 2.27 5667 0.268 6700.294 734 2.56 6401 28-3 SD 0.005 11.5 0.58 1449 0.105 263 % CV 18 18 2626 39 39

Efficiency of Delivery

Tissue permeation and deposition of Imiquimod are summarized in Table 10and presented in units of percent of applied dose and calculated ng/cm²following a theoretical dose of 5 mg composition/cm².

Tissue Permeation (Receptor Phase Levels).

With reference to Table 10, Column 1, Sub-Column A, tissue permeation(receptor phase levels) after 24 hours ranged from 0.015 to 0.026percent of the applied dose of Imiquimod.

Dermal Deposition.

With reference to Table 10, Column 3, Sub-Column A, dermal deposition ofImiquimod from the evaluated compositions ranged from 0.118 to 0.296percent of the applied dose. Composition 3537-25-4 and 3537-26-1 had thehighest efficiency of Imiquimod dermal deposition with 0.269 and 0.296percent of the applied dose respectively. The lowest efficiency ofImiquimod dermal deposition was produced by Composition 3537-25-2 with0.118% percent of the applied dose.

Epidermal Deposition.

With reference to Table 10, Column 2, Sub-Column A, epidermal depositionof Imiquimod from the evaluated compositions ranged from 1.80 to 3.76percent of the applied dose. Compositions 3537-25-4 and 3537-26-1 hadthe highest efficiency of Imiquimod epidermal deposition with 2.79 and3.76 percent of the applied dose, respectively. The lowest efficiency ofImiquimod epidermal deposition was generated by Composition 3537-25-2.

Total Amount Delivered

Tissue Permeation (Receptor Phase Levels).

With reference to Table 10, Column 1, Sub-Column B, the total amount ofImiquimod delivered from a composition is dependent upon theconcentration of Imiquimod in the product as well as the efficiency ofdelivery (percent of applied dose). Calculated mass of Imiquimodpermeating the tissue following a dose of 5 mg composition per squarecentimeter of skin for 24 hours (receptor phase levels) ranged from 37.2to 60.1 ng/cm² of Imiquimod. Compositions 3537-25-2 and 3537-26-2 hadthe highest delivery of Imiquimod with 46.2 and 60.1 ng/cm²,respectively, whereas the lowest efficiency of Imiquimod delivery waswith 3537-25-5. A kinetic profile of tissue permeation is presented inFIG. 3, where the cumulative tissue permeation of Imiquimod in units ofng/cm² is plotted against time in hours.

Dermal Deposition.

With reference to Table 10, Column 3, Sub-Column B, the calculatedImiquimod dermal deposition ranged from 295 to 741 ng/cm². Compositions3537-25-4 and 3537-26-1 had the highest Imiquimod dermal deposition with672 and 741 ng/cm², respectively. Composition 3537-25-2 Compositionproduced the lowest Imiquimod dermal deposition, 295 ng/cm². Theseresults are presented graphically in FIG. 4, which shows dermal levelsof Imiquimod following 24 hour duration of topical exposure in unit(s)of ng/cm².

Epidermal Deposition.

With reference to Table 10, Column 2, Sub-Column B, the calculatedImiquimod epidermal deposition ranged from 4,492 to 9,405 ng/cm².Compositions 3537-25-4 and 3537-26-1 had the highest Imiquimod epidermaldeposition with 6,971 and 9,405 ng/cm², respectively. Composition3537-25-2 generated the lowest Imiquimod epidermal deposition, 4,492ng/cm². These results are presented graphically in FIG. 5, which showsepidermal levels of Imiquimod following 24 hour duration of topicalexposure in unit(s) of ng/cm².

Dermis and Receptor (Combined Values).

With reference to Table 10, Column 4, Sub-Column B, the total amount ofImiquimod present in the dermal and receptor compartments was assessedby calculating the total calculated mass/cm² [ng/cm²] for a compositiondose of 5 mg/cm² present in the dermis (D) and receptor (R)compartments. Subsequently, the mean values of six replicates weredetermined and defined as D+R. The calculated mean D+R values providedan indication of the total amount of API that penetrated the epidermis.Mean D+R ranged from 341 to 781 ng/cm² of Imiquimod. Compositions3537-25-4 and 3537-26-1 yielded the highest D+R values, respectively.The lowest D+R was associated with Composition 3537-25-2. These resultsare presented graphically in FIG. 6, which shows D+R levels of Imiquimodfollowing 24 hour duration of topical exposure in unit(s) of ng/cm².

CONCLUSIONS

Data from this study demonstrate a trend in the efficiency of deliveryof Imiquimod. Imiquimod delivery, expressed as a sum of all the deliveryvalues for each of the three evaluated compartments, has a consistentresponse to the addition of Tazarotene: Delivery of Imiquimod increaseswith the addition of Tazarotene.

With reference to FIG. 2, showing the cumulative penetration ofImiquimod, the data consistently show that any addition of tazarotene tothe composition will improve the penetration of imiquimod, surprisingly,even at concentrations as much as 10 times lower (0.01% (w/w)) than theconcentration at which tazarotene is currently in clinical use (0.1%(w/w)). Unexpectedly, compositions including doses of tazarotene as lowas 0.01% appear to provide for similar levels of penetration as comparedto compositions including a 0.1% concentration of tazarotene. Also,surprisingly, it appears that concentrations of tazarotene that arehigher (1%) or relatively higher as compared to imiquimod (1:5 ratio)were less effective than lower concentrations.

Another unexpected finding was associated with the positive control(3537-28-3), which contained DMSO, but apart from the solvent wasidentical to composition 3537-25-5. DMSO based controls are used becausethey usually yield higher delivery of actives through the skin. In thiscase, the DMSO control (which included Tazarotene) did not give a higherdegree of penetration, indicating that imiquimod delivery is independentof the choice of solvent, but instead is due to the addition oftazarotene. Indeed, as compared to the sample including Imiquimodwithout tazarotene (3537-25-2), all test samples including anyconcentration of tazarotene were found to improve penetration ofImiquimod.

As contemplated by the present inventor, composition including imiquimodand tazarotene have increased penetration, as compared to imiquimodindividually. It is believed that the increased penetration can becorrelated to an increased effectiveness of imiquimod. Without wishingto be bound by theory or mechanism, the increased penetration isbelieved to result from an ability of tazarotene to decrease thethickness of a layer of keratin in the virally infected cells.Tazarotene also decreases keratinocyte proliferation and increases thematuration phase of the virally infected cells thus thinning the thickskin that often covers warts. The combination also allows for a dilutionof the tazarotene and its potential for local irritancy. Indeed, withthe surprising efficacy at lower concentrations of tazarotene, certainembodiments of the composition can be readily prepared to limitirritancy and/or for areas prone to irritation. The compositions of thepresently-disclosed subject matter will allow for increased tolerance,efficacy, compliance, and ease of use. When the imiquimod and tazaroteneare used separately, the effects of both are diminished, and if appliedat different points in time there is a decrease in compliance as well asthe loss of the beneficial effect noted when utilized simultaneously incompositions of the presently-disclosed subject matter.

As noted herein, synergistic clinical results are achieved by combiningan imidazoquinoline compound and a retinoid agent in a singlecomposition. Without wishing to be bound by theory or mechanism, inaddition to benefits achieved due to increased penetration of theimidazoquinoline compound, as facilitated by the retinoid agent, eachcomponent of the composition has an active role in treating thecondition of interest, and each improves the effect of the other byvirtue of being provided in a single composition for administration. Forexample, in addition to increasing the penetration of theimidazoquinoline compound, the retinoid agent has an effect in treatingthe condition of interest, and such effect is improved in the presenceof the imidazoquinoline compound. Similarly, in addition to havingincreased penetration in the presence of the retinoid agent, theimidazoquinoline compound has an improved effect in treating thecondition of interest in the presence of the retinoid agent. In thisregard, the combination of the imidazoquinoline compound and theretinoid agent can achieve synergistic results in the treatment of acondition affecting skin and/or a mucosal surface of a subject, whichare in addition to mere additive effect. In some embodiments, thesynergistic results are in addition to effects resulting from increasedpenetration of the imidazoquinoline compound in the presence of theretinoid agent. As is further contemplated, and without wishing to bebound by theory or mechanism, it believed that biochemical chemicalpathways related to conditions of interest are impacted in a synergisticmanner in the presence of both the imidazoquinoline compound and theretinoid agent (e.g., imiquimod and tazarotene), such that theimidazoquinoline compound has improved efficacy in the presence of theretinoid agent and, similarly, the retinoid agent has improved efficacyin the presence of the imidazoquinoline compound.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification, including those set forth in the following list, areherein incorporated by reference to the same extent as if eachindividual publication, patent, or patent application was specificallyand individually indicated to be incorporated by reference.

REFERENCES

DePaula, Martins, and Bentley, “Development and validation of HPLCmethod for imiquimod determination in skin penetration studies,” BiomedChromatogr 22(12): 1416-23 (2008).

Jackson and Callen, (In Press) Chapter 128: Immunomodulators. InBolognia, Jorizzo, and Rapini Dermatology, 3d. Edition.

Owens M L, Bridson W E, Smith S L, Myers J A, Fox T L, and Wells T M,“Percutaneous penetration of Aldara cream, 5% during the topicaltreatment of genital and perianal warts,” Prim Care Update Ob Gyns.5(4):151 (1998).

Skelly, J. P., Shah, V. P., Maibach, H. I., Guy, R. H., Wester, R. C.,Flynn, G. L. and Yacobi, A. (1987). “FDA and AAPS report of the workshopon principles and practices of in-vitro percutaneous penetrationstudies: Relevance to bioavailability and bioequivalence.”Pharmaceutical Research 4(3): 265-267.

What is claimed is:
 1. A composition, comprising: imiquimod at a finalconcentration of between about 0.1% (wt/wt) and about 10% (wt/wt);tazarotene at a final concentration of between about 0.001% (wt/wt) andabout 1% (wt/wt); and at least one additional ingredient selected fromthe group consisting of salicylic acid, urea, alpha-hydroxy acid, andbeta-hydroxy acid at a final concentration of between about 0.5% (wt/wt)and about 70% (wt/wt).
 2. The composition of claim 1, wherein the ratioof the concentration of tazarotene to the concentration of imiquimod isless than 1:5.
 3. The composition of claim 2, wherein the ratio of theconcentration of tazarotene to the concentration of imiquimod is lessthan 1:10.
 4. The composition of claim 2, wherein the imiquimod is at afinal concentration of between about 0.1% (wt/wt) and about 8% (wt/wt).5. The composition of claim 2, wherein the imiquimod is at a finalconcentration of between about 0.1% (wt/wt) and less than about 8%(wt/wt).
 6. The composition of claim 2, wherein the tazarotene is at afinal concentration of between about 0.001% (wt/wt) and about 0.1%(wt/wt).
 7. The composition of claim 2, wherein the tazarotene is at afinal concentration of between about 0.001% (wt/wt) to less than about0.1% (wt/wt).
 8. The composition of claim 2, wherein the tazarotene isat a final concentration of between about 0.001% (wt/wt) and about 0.01%(wt/wt).
 9. The composition of claim 1, wherein the at least oneadditional ingredient is salicylic acid.
 10. The composition of claim 9,wherein the salicylic acid increases penetration of the composition. 11.The composition of claim 10, wherein the ratio of the concentration oftazarotene to the concentration of imiquimod is less than 1:10.
 12. Thecomposition of claim 1, wherein the at least one additional ingredientis urea.
 13. The composition of claim 12, wherein the urea increasespenetration of the composition.
 14. The composition of claim 13, whereinthe ratio of the concentration of tazarotene to the concentration ofimiquimod is less than 1:10.
 15. The composition of claim 1, wherein theat least one additional ingredient is alpha-hydroxy acid.
 16. Thecomposition of claim 15, wherein the alpha-hydroxy acid increasespenetration of the composition.
 17. The composition of claim 16, whereinthe ratio of the concentration of tazarotene to the concentration ofimiquimod is less than 1:10.
 18. The composition of claim 1, wherein theat least one additional ingredient is beta-hydroxy acid.
 19. Thecomposition of claim 18, wherein the beta-hydroxy acid increasespenetration of the composition.
 20. The composition of claim 19, whereinthe ratio of the concentration of tazarotene to the concentration ofimiquimod is less than 1:10.